Sunday, April 17, 2016

One of the most interesting stories currently is the collision of sports and politics on the question of Latvian-invented meldonium. US News carries an AP story reporting that Russian President Vladimir Putin has gone on record as stating that Meldonium is not an athletic-performance-enhancing drug.

See the following link to a video at the above US News article which contains an excellent interview of Dr. Michael White, UConn School of Pharmacy, regarding meldonium, trade-named as Mildronate:

The simple fact is that a 20-capsule package of meldonium at 250 mg per capsule is an OTC (over-the-counter) medication that can be purchased without a prescription in pharmacies in Latvia (perhaps in Russia too, we do not know). Meldonium is in our view quite comparable to ubiquitous vitamin and nutritional supplements and has been available for purchase for many years.

There is no evidence that taking meldonium somehow magically "enhances" athletic performance. It may make your heart healthier, just as some vitamin or similar supplements, or even certain foods, also claim to do, but that is by no means "drug misuse" of the kind that should be prohibited in athletics.

In the interview cited above, Dr. Michael White, who otherwise gives a straightforward, very informative interview, asks why Sharapova, who spends much of her time in the USA, does not take a "comparable" USA-FDA (Food & Drug Administration) approved "heart medication" rather than meldonium. Why should she do that if she has been taking meldonium without side effects for years? Nationalistic provincialism should not mark the pharmaceutical field.

As someone who worked for years in the pharmaceutical industry, here is our very personal but we hope instructive take on a further answer to Dr. White's question about what substances we can take. It is all about money.

We are a high energy individual, so that when meldonium first came to our attention, it looked to us like an interesting alternative substance that appeared capable of strengthening the heart and had no known side effects, so we obtained meldonium as the product Mildronāts - Grindeks, perfectly legally, prescription-free, and OTC from Latvia, a European Union Member State. We have no qualms about using it in Germany, another EU Member State, which in our view can not prohibit us from using such a medication freely available in the EU, even if the substance itself may not be approved for sale in Germany itself. That would otherwise contradict the "single market" principle. We are here, after all, not dealing with some kind of illegal drug.

In our short experience we can report that meldonium seems to have a very positive effective on lowering our high blood pressure and thus far shows no negative side effects whatsoever. There may even be a positive side effect.

A package of 20 such 250mg capsules of meldonium costs about €6, so let us say ca. €10 per month if taken as we take them, at one capsule a day, even though 2 are recommended as the normal dosage. That is a cost of ca. two-thirds less than what we would have to pay out of pocket for our non-generic angiotensin II receptor blocker, since insurance covers only cheap generics -- in our experience not always comparably effective. The annual cost is thus $120 instead of $360. Quite a bit of money for an average person.

As a sample of the prices in force for a high blood pressure medication such as e.g. Micardis -- that is the brand version while the generic is called Telmisartan -- see PharmacyChecker.com, which also appends the following footnotes significant for money questions and borderline legal issues:

""*The total price includes shipping fees which typically cover an entire order....
**U.S. Law and Drug Safety: U.S. government officials have stated that individuals who order non-controlled prescription drugs from Canada or other foreign sources (up to a three-month supply) for their own use are not being pursued or prosecuted. However, it is technically not legal for individuals to import most prescription drugs. The U.S. FDA regulates the safety and efficacy of medications sold in U.S. pharmacies. Medications dispensed from outside the U.S. are regulated for safety and efficacy by pharmaceutical/pharmacy regulatory authorities in other countries. Read how regulations may differ by country.Coverage by Insurance: For a drug to be reimbursable from a health reimbursement account or flexible spending account it must be approved for sale in the U.S. and prescribed by a licensed U.S. physician, although drugs which you personally import are typically not reimbursable. If you have pharmacy insurance coverage, you may want to check with your benefits administrator to determine whether drugs ordered from outside the U.S. will be covered or reimbursed."

Why is meldonium not available for sale in Western nations? There appears to be a simple explanation. It is not a home-grown product and is priced reasonably. Hence, profits via meldonium would be much lower for indigenous pharmaceutical companies who would have to pay patent royalties on a licensed product sold much more cheaply than their own overly priced, patented, but perhaps nevertheless inferior remedies. We are reminded here of the many actions taken by Apple, Inc. to keep competing, in part, better, smartphones and tablets out of the country. The monopoly principle is the same. Keep competition out.

The meldonium controversy is thus conceivably not a medical issue at all, but rather an issue of institutional power, money and monopoly pharmaceutical markets.

The USA's FDA and similar institutions elsewhere function as "economic barriers to entry". Even if a drug has been clinically tested and approved elsewhere, every nation persists on making their own studies in determining the licensing of substances, a costly ever-duplicating process paid for by the taxpayers, who have no say in the matter, and who may even be paying top dollar for inferior pharmaceutical substances at their own local pharmacies.

When institutions such as the World Anti-Doping Agency (WADA) start blacklisting substances just because they are being used -- blacklisting without any evidence that they do in fact increase athletic performance unfairly, then things are askew in the systems of control that govern competitive sports, as we already know from negative examples at the NCAA, the FIFA and the Olympic movement. Competitive sports are dominated by self-serving monopolies, often abetted by clueless lawmakers and courts who accord such sports organizations special advantages, to which they should not be entitled at all. EVERYONE is "in business". EVERYONE.

The competitive sports world has become -- or perhaps it always has been -- a golden goose for too many organizations and their officers at the cost of the competing athletes. The private WADA is surely no exception in this regard, as its monopolistic practises have come under increasing scrutiny (see the Wikipedia for examples).

Moreover, all of these organizations try to expand their powers as much as possible so that they can tell other people what they are supposed to do. Why people have that need for power is something we have never understood.

Indeed, it is the athletes who are usually being punished by these "ruling bodies" and not those who run athletics. It is a bizarre system of top-down injustice in which the ruling organizations and institutions control the lives of athletes for their own selfish self-serving and self-sustaining ends.

And now perhaps someone in Brussels or Berlin can explain to us why in the alleged "single market" of the European Union, it is virtually impossible to order prescription-free meldonium online, as it is not delivered by Latvian pharmacies outside of the territory of Latvia, as far as we have been able to determine. Mildronate used to be available through Amazon.de. No longer. Its sale is conceivably being blocked on the orders of someone.

Moreover, we have found a few links here and there online that seem to point to meldonium "teasers" -- you are warned -- i.e. websites not actually selling meldonium but purporting to do so, and perhaps acting on behalf of other parties to discover who is taking meldonium and who is not.

Sunday, April 10, 2016

We were happy to read that the ABBYY FineReader engine has been used to preserve 4 million pages in 20 languages at the National Library of Latvia. Much material is available for public viewing.
This is not an ad, just info. See that page for further links.

Ivars Kalviņš, the Latvian Inventor of meldonium (also known as mildronāts, Mildronate, Quaterine, MET-88, or THP) has defended the safety of the allegedly performance-enhancing drug that has brought Russian tennis star Maria Sharapova into an alleged doping crossfire, very likely unjustly, because, as Kalvins of Latvia's Institute of Organic Synthesis has stated, there is no clinical evidence that taking meldonium improves athletic performance per se.

Meldonium is a curious case because the substance was only put on the athletically prohibited list of drugs this year, in 2016, whereas the medication was already invented in the 1980s and used for livestock. Clinical trials on humans were conducted in 2005 for its use as a heart medication. As written by Eric Niiler at Wired (yes, two i's) in The Quirky History of Meldonium, From a Latvian Lab to Maria Sharapova:

As Niiler writes further, the World Anti-Doping Authority (WADA) has stated off the record that meldonium was put on the prohibited list because it is allegedly "an energy efficiency catalyst that increases oxygen uptake, enhancing stamina and endurance." WADA is being careful in its statements on the record because they are in hot water legally, having no evidence that meldonium improves athletic performance, nor is there any evidence that meldonium is harmful to athletes -- quite the contrary, all available evidence indicates that meldonium, as a CYTOPROTECTIVE SUBSTANCE -- is beneficial for health -- perhaps for everyone!

"Kalvins says the [Sharapova] ban is literally a crime. “It’s a violation of human rights,” he says. “The sportsmen should be able to protect their health. We are living in an era of evidence-based medicine, so there are not any other new data supporting the ban.” He calls the prohibition “sudden” and “a surprise.”" [emphasis added]

In fact, meldonium is a registered drug in Latvia, Russia and East European countries and has been prescribed for heart patients for years because -- if taken as indicated under the supervision of a physician -- it has proven beneficial not only for heart indications but for health in general, as detailed at the end of this posting.

The slow-moving U.S. Food and Drug Administration has not approved it yet. See Flash - Inventor defends safety, questions ban on Sharapova drug - France 24. It is also not yet approved in Germany, in spite of clinical trials that were published already in 2010 in Seminars in Cardiovascular Medicine, 2010; 16:3. That failing in the USA and Germany, of course, may have much more to do with big money and pharmaceutical politics rather than the honest attempt to provide the best medicine to citizens via new substances, especially if the patents to those substances are owned by foreign firms.

At any rate, as a legal matter, it simply can not be the casethat substances that are beneficial to the heart and the circulatory system are put on lists of substance prohibitions for athletes -- just because athletes use them beneficially. That is really quite absurd.

Many athletes surely stress their hearts more than your average person and thus taking vitamins or other medications to protect their hearts and health surely is not "doping" per se at all. We should in fact rather encourage athletes to take supplements which are beneficial to them and their organs and which make them stronger, presuming the drugs are not harmful.

Better heart health could of course result in better athletic performance in any sport, and especially so in tennis, which puts a lot of stress on the circulatory system, but to ban substances that improve an athlete's overall health can not be the purpose of prohibitory athletic doping laws. That simply goes too far in terms of sports officials interfering with people's free choice and, paradoxically, likely HARMING their health through prohibition.

There must be a line drawn between permissible supplements that improve the health of athletes as opposed to drugs such as steroids that are used primarily to enhance muscle size and thus to gain an unfair athletic advantage in strength sports. Moreover, steroid abuse has been shown to be dangerous to the health of athletes. But what about other "supplements"?

We ourselves find that eating honey and peanut butter sandwiches prior to tennis matches or other athletic endeavors appears to be beneficial for winning or losing -- for us. Calories to burn as it were. Dehydration can also be a severe problem for athletic performance and we swear by Coca-Cola (R) in such cases. Who is anyone to prohibit us from doing that?! In other words, there must be sensible limits to drug doping law prohibitions.

The world is constantly moving forward and new discoveries are being made every day that have the potential to improve human health. There is no way that all such new discoveries can be prohibited for athletes. That would be unsupportable discrimination against athletes. Indeed, the athletes may be serving in the course of their competitions as models for the rest of us, who down the road may in fact find ourselves taking the same substances to lead a better life. Meldonium certainly looks like one of those substances.

Be that all as it may, meldonium is manufactured only in Riga, Latvia by the pharmaceutical firm Grindeks (Grindex), and prescriptions of the drug have shot up considerably since the Sharapova case became public.

As written at France24 about the clever Mayor of Riga and meldonium, and we would not be surprised if tourist traffic to Riga increased as a result:

"Meanwhile, the mayor of Riga, Nils Usakovs has turned the controversy over the drug into a cheeky promotional initiative.

On his Twitter and Instagram accounts, he has mocked up a holiday-style poster, decorated with swimsuit-clad women, with the slogan: 'Welcome to Riga, meldonium home city!'"

"Despite «Grindeks»’s submitted arguments, evidence and justifications, the World Anti-Doping Agency (WADA) included meldonium in the Prohibited list. In accordance with the results of the extended research, «Grindeks» has a firm conviction that meldonium should not be included in the Prohibited list. It is unclear to «Grindeks» why the WADA included meldonium in the Prohibited list, because it never gave any explanation of this decision. The company will continue to use all the options and will stand up for to the exclusion of meldonium from the WADA’s Prohibited list.

Mildronate® is a registered trademark of the JSC «Grindeks». Its active pharmaceutical ingredient (or active substance) is meldonium which is responsible for the pharmacological and therapeutic effects of Mildronate®. It should be noticed that inclusion of meldonium (Mildronate®) in the Prohibited list doesn’t change the fact that it is a medicine of high quality, safety and efficacy. Until now it has been available to everyone, including athletes, to prevent the negative effects caused by physical and psycho-emotional overload.

Mildronate® is widely used in the clinical practice. During increased physical activity, it restores the oxygen balance of tissue cells as well as activating the metabolic processes that result in lower requirements of oxygen consumption for energy production. Mildronate® is widely recognized by health care professionals and patients, and this may include athletes as well.

Mildronate® is mostly prescribed for patients to treat heart and cardiovascular diseases, including stable angina pectoris, chronic heart failure (NYHA I-III functional class), cardiomyopathy, functional cardiovascular disorders; also when there are acute and chronic ischemic brain blood circulation disorders, reduced working capacity, physical and psycho-emotional overload as well as during the recovery period after cerebrovascular disorders, head injury and encephalitis.

Depending on the patient’s health condition, the treatment course of meldonium preparations may vary from 4 to 6 weeks. The treatment course can be repeated twice or thrice a year. Only physicians can follow and evaluate patient health condition and state whether the patient should use meldonium for a longer period of time or not according to the information provided in the patient leaflet and summary of product characteristics.

Meldonium is a cytoprotective substance, which is used to prevent death of ischemic cells, and not to increase performance of normal cells. The mechanism of action of meldonium is based on limitation of carnitine biosynthesis, which leads to deceleration of fatty acid oxidation and activation of glycolysis. Unlike carnitine, meldonium doesn’t cause increase of muscle mass and physical properties. Meldonium decreases cellular damage from ischemia by reducing accumulation of detergent substances (acylcarnitine and acyl-coenzyme A) in the mitochondria. It means that meldonium reduces the ability of an organism to use fatty acids as its energy source. This is important in the treatment of pathologies associated with heart muscle ischemia (stenocardia, heart failure), because in these cases the heart is not getting enough oxygen and nutrients. Consequently, meldonium is a cytoprotective substance, which is used to prevent death of ischemic cells, and not to increase performance of normal cells. It means that meldonium cannot improve athletic performance, but it can stop tissue damage in the case of ischemia. That is why this therapeutic drug is not a doping agent.

Good safety profile of Mildronate® should be particularly emphasized. This is one of the key factors explaining its wide recognition among the doctors and patients. The Mildronate®’s safety is confirmed by its periodic safety update records and the results of published clinical studies. Based on available data, no adverse reactions related to Mildronate®’s use in athletes have been registered."

Meldonium looks pretty good to us, and WADA has clearly made a mistake in putting a substance on the prohibited list which has not been proven to be harmful nor has it been proven that it confers an unfair advantage in sports.

Moreover, as a personal matter and on behalf of people who might be helped to lead better lives with meldonium, we want to know why the substance is not available in the USA and Germany, where the local pharmaceutical company monopolies are reaping gigantic profits by providing us with what may turn out to be less effective cardiovascular substances than meldonium.

"Gravitational Waves Detected 100 Years After Einstein's Prediction

See also: LIGO Hanford Press ReleaseLIGO Opens New Window on the Universe with Observation of Gravitational Waves from Colliding Black HolesWASHINGTON, DC/Cascina, ItalyFor the first time, scientists have observed ripples in the fabric of
spacetime called gravitational waves, arriving at the earth from a
cataclysmic event in the distant universe. This confirms a major
prediction of Albert Einstein’s 1915 general theory of relativity and
opens an unprecedented new window onto the cosmos.Gravitational waves carry information about their dramatic origins
and about the nature of gravity that cannot otherwise be obtained.
Physicists have concluded that the detected gravitational waves were
produced during the final fraction of a second of the merger of two
black holes to produce a single, more massive spinning black hole. This
collision of two black holes had been predicted but never observed.The gravitational waves were detected on September 14, 2015 at 5:51
a.m. Eastern Daylight Time (09:51 UTC) by both of the twin Laser
Interferometer Gravitational-wave Observatory (LIGO) detectors, located
in Livingston, Louisiana, and Hanford, Washington, USA. The LIGO
Observatories are funded by the National Science Foundation (NSF), and
were conceived, built, and are operated by Caltech and MIT. The
discovery, accepted for publication in the journal Physical Review
Letters, was made by the LIGO Scientific Collaboration (which includes
the GEO Collaboration and the Australian Consortium for Interferometric
Gravitational Astronomy) and the Virgo Collaboration using data from the
two LIGO detectors.Based on the observed signals, LIGO scientists estimate that the
black holes for this event were about 29 and 36 times the mass of the
sun, and the event took place 1.3 billion years ago. About 3 times the
mass of the sun was converted into gravitational waves in a fraction of a
second—with a peak power output about 50 times that of the whole
visible universe. By looking at the time of arrival of the signals—the
detector in Livingston recorded the event 7 milliseconds before the
detector in Hanford—scientists can say that the source was located in
the Southern Hemisphere.According to general relativity, a pair of black holes orbiting
around each other lose energy through the emission of gravitational
waves, causing them to gradually approach each other over billions of
years, and then much more quickly in the final minutes. During the final
fraction of a second, the two black holes collide into each other at
nearly one-half the speed of light and form a single more massive black
hole, converting a portion of the combined black holes’ mass to energy,
according to Einstein’s formula E=mc2. This energy is emitted as a final strong burst of gravitational waves. It is these gravitational waves that LIGO has observed.The existence of gravitational waves was first demonstrated in the
1970s and 80s by Joseph Taylor, Jr., and colleagues. Taylor and
Russell Hulse discovered in 1974 a binary system composed of a pulsar in
orbit around a neutron star. Taylor and Joel M. Weisberg in 1982 found
that the orbit of the pulsar was slowly shrinking over time because of
the release of energy in the form of gravitational waves. For
discovering the pulsar and showing that it would make possible this
particular gravitational wave measurement, Hulse and Taylor were awarded
the Nobel Prize in Physics in 1993.The new LIGO discovery is the first observation of gravitational
waves themselves, made by measuring the tiny disturbances the waves make
to space and time as they pass through the earth.“Our observation of gravitational waves accomplishes an ambitious
goal set out over 5 decades ago to directly detect this elusive
phenomenon and better understand the universe, and, fittingly, fulfills
Einstein’s legacy on the 100th anniversary of his general theory of
relativity,” says Caltech’s David H. Reitze, executive director of the
LIGO Laboratory.The discovery was made possible by the enhanced capabilities of
Advanced LIGO, a major upgrade that increases the sensitivity of the
instruments compared to the first generation LIGO detectors, enabling a
large increase in the volume of the universe probed—and the discovery of
gravitational waves during its first observation run. The US National
Science Foundation leads in financial support for Advanced LIGO. Funding
organizations in Germany (Max Planck Society), the U.K. (Science and
Technology Facilities Council, STFC) and Australia (Australian Research
Council) also have made significant commitments to the project. Several
of the key technologies that made Advanced LIGO so much more sensitive
have been developed and tested by the German UK GEO collaboration.
Significant computer resources have been contributed by the AEI Hannover
Atlas Cluster, the LIGO Laboratory, Syracuse University, and the
University of Wisconsin- Milwaukee. Several universities designed,
built, and tested key components for Advanced LIGO: The Australian
National University, the University of Adelaide, the University of
Florida, Stanford University, Columbia University of the City of New
York, and Louisiana State University.“In 1992, when LIGO’s initial funding was approved, it represented
the biggest investment the NSF had ever made,” says France Córdova, NSF
director. “It was a big risk. But the National Science Foundation is
the agency that takes these kinds of risks. We support fundamental
science and engineering at a point in the road to discovery where that
path is anything but clear. We fund trailblazers. It’s why the U.S.
continues to be a global leader in advancing knowledge.”LIGO research is carried out by the LIGO Scientific Collaboration
(LSC), a group of more than 1000 scientists from universities around the
United States and in 14 other countries. More than 90 universities and
research institutes in the LSC develop detector technology and analyze
data; approximately 250 students are strong contributing members of the
collaboration. The LSC detector network includes the LIGO
interferometers and the GEO600 detector. The GEO team includes
scientists at the Max Planck Institute for Gravitational Physics (Albert
Einstein Institute, AEI), Leibniz Universität Hannover, along with
partners at the University of Glasgow, Cardiff University, the
University of Birmingham, other universities in the United Kingdom, and
the University of the Balearic Islands in Spain.“This detection is the beginning of a new era: The field of
gravitational wave astronomy is now a reality,” says Gabriela González,
LSC spokesperson and professor of physics and astronomy at Louisiana
State University.LIGO was originally proposed as a means of detecting these
gravitational waves in the 1980s by Rainer Weiss, professor of physics,
emeritus, from MIT; Kip Thorne, Caltech’s Richard P. Feynman Professor
of Theoretical Physics, emeritus; and Ronald Drever, professor of
physics, emeritus, also from Caltech.“The description of this observation is beautifully described in the
Einstein theory of general relativity formulated 100 years ago and
comprises the first test of the theory in strong gravitation. It would
have been wonderful to watch Einstein’s face had we been able to tell
him,” says Weiss.

“With this discovery, we humans are embarking on a marvelous new
quest: the quest to explore the warped side of the universe—objects and
phenomena that are made from warped spacetime. Colliding black holes and
gravitational waves are our first beautiful examples,” says Thorne.Virgo research is carried out by the Virgo Collaboration, consisting
of more than 250 physicists and engineers belonging to 19 different
European research groups: 6 from Centre National de la Recherche
Scientifique (CNRS) in France; 8 from the Istituto Nazionale di Fisica
Nucleare (INFN) in Italy; 2 in The Netherlands with Nikhef; the Wigner
RCP in Hungary; the POLGRAW group in Poland; and the European
Gravitational Observatory (EGO), the laboratory hosting the Virgo
detector near Pisa in Italy.Fulvio Ricci, Virgo Spokesperson, notes that, “This is a significant
milestone for physics, but more importantly merely the start of many new
and exciting astrophysical discoveries to come with LIGO and Virgo.”

Bruce Allen, managing director of the Max Planck Institute for
Gravitational Physics (Albert Einstein Institute), adds, “Einstein
thought gravitational waves were too weak to detect, and didn’t believe
in black holes. But I don’t think he’d have minded being wrong!”“The Advanced LIGO detectors are a tour de force of science and
technology, made possible by a truly exceptional international team of
technicians, engineers, and scientists,” says David Shoemaker of MIT,
the project leader for Advanced LIGO. “We are very proud that we
finished this NSF-funded project on time and on budget.”At each observatory, the two-and-a-half-mile (4-km) long L-shaped
LIGO interferometer uses laser light split into two beams that travel
back and forth down the arms (four-foot diameter tubes kept under a
near-perfect vacuum). The beams are used to monitor the distance between
mirrors precisely positioned at the ends of the arms. According to
Einstein’s theory, the distance between the mirrors will change by an
infinitesimal amount when a gravitational wave passes by the detector. A
change in the lengths of the arms smaller than one-ten-thousandth the
diameter of a proton (10-19 meter) can be detected.“To make this fantastic milestone possible took a global
collaboration of scientists—laser and suspension technology developed
for our GEO600 detector was used to help make Advanced LIGO the most
sophisticated gravitational wave detector ever created,” says Sheila
Rowan, professor of physics and astronomy at the University of Glasgow.

Independent and widely separated observatories are necessary to
determine the direction of the event causing the gravitational waves,
and also to verify that the signals come from space and are not from
some other local phenomenon.Toward this end, the LIGO Laboratory is working closely with
scientists in India at the Inter-University Centre for Astronomy and
Astrophysics, the Raja Ramanna Centre for Advanced Technology, and the
Institute for Plasma to establish a third Advanced LIGO detector on the
Indian subcontinent. Awaiting approval by the government of India, it
could be operational early in the next decade. The additional detector
will greatly improve the ability of the global detector network to
localize gravitational-wave sources.“Hopefully this first observation will accelerate the construction of
a global network of detectors to enable accurate source location in the
era of multi-messenger astronomy,” says David McClelland, professor of
physics and director of the Centre for Gravitational Physics at the
Australian National University. Additional video and image assets can be found here: http://mediaassets.caltech.edu/gwaveCaltech
Kathy Svitil
Director of News and Content Strategy
626-676-7628 (cell)
ksvitil@caltech.edu